Abstract Significance: This proposal has the potential to impact a large number of patients since colorectal cancer (CRC) is the 3rd leading cause of cancer deaths in both genders. K-Ras is mutated in approximately 40% of all CRCs and this mutation makes tumors resistant to EGFR-targeted therapies. Our studies aim to develop novel strategies for treatment of tumors with K-Ras mutations. Additionally, we propose that our treatment strategies will have a high therapeutic index, since we are targeting proteins that are expendable for normal growth, but required for malignancy. We also anticipate that our findings will be applicable to other tumors with mutant Ras proteins, which constitute up to 30% of all human malignancies. Background: We have determined that 5' AMP-activated protein kinase (AMPK), peroxisome proliferator- activated receptor gamma coactivator 1-beta (PGC1?), and estrogen-related receptor alpha (ERR?) are novel regulators of tumor metabolism in K-Ras mutant CRCs. PGC1? is a transcriptional co-activator and ERR? is a transcription factor that are present in highly metabolic tissues, such as heart, skeletal muscle, brain and brown adipose tissue, where they interact to transcribe genes involved in metabolism and mitochondrial biogenesis. PGC1? and ERR? are dramatically over-expressed in CRC cell lines and human liver metastases compared to non-transformed human colon epithelial cells (HCECs) and normal human colon tissue, respectively. AMPK, a critical regulator of energy homeostasis, is a potent regulator of PGC1?, ERR?, and tumor survival. Research Plan: In this application, we present preliminary data on the critical role of AMPK, PGC1?, and ERR? as novel regulators of tumor metabolism and survival in K-Ras mutant CRCs and we hypothesize that these are promising targets for the development of novel treatment strategies because they are expendable for normal cell growth. To test this hypothesis, first, we will examine the role of PGC1? and ERR? downstream effector Ras-related GTP-binding protein D (RagD), a positive regulator of mTORC1 signaling and tumor growth. Second, we will characterize the critical regulatory role of AMPK on PGC1? activity. Lastly, we will assess the role of PGC1?, ERR?, and an ERR? inhibitor in metastatic disease using the orthotopic cecal implantation mouse model of metastasis. This proposal will advance our knowledge of these underexplored metabolic effectors that are required for K-Ras mutant CRCs and have the potential for the development of several types of novel therapeutics. Career Development: I have worked closely with my mentors to create a scientific and career development plan designed to help me transition to independence as a physician-scientist. Specifically, I will gain valuable training in metabolic regulation of cancer growth, models of metastasis, leadership skills, grantsmanship, and ethical research. My mentorship committee consists of outstanding faculty members with expertise in mentoring junior faculty members, CRC research, and training of physician-scientists.